KEY POINTS
- This mechanistic study used mouse models, intestinal organoids and IEC-6 cells to determine whether S100A8/A9—calprotectin—is a driver rather than simply a biomarker of radiation-induced intestinal injury. Mice received abdominal irradiation at 8 Gy for temporal profiling, 10 Gy for mechanistic/repair experiments and 12 Gy for survival studies.
- S100A8/A9 rose rapidly after irradiation, increased in a dose-dependent manner and peaked on day 4, before returning toward baseline by day 8. Immunofluorescence localized most of the signal to Ly6G-positive neutrophils infiltrating intestinal crypts, rather than macrophages.
- Investigators inhibited S100A8/A9 signaling using paquinimod 10 mg/kg/day, which blocks S100A9 interactions with TLR4 and RAGE. After lethal 12-Gy abdominal irradiation, all control mice had died by day 7, whereas only 20% of paquinimod-treated mice died, corresponding to 80% survival in the treated group.
- At 10 Gy, the protective effect became evident during the regenerative phase. By day 4, paquinimod reduced crypt-villus destruction, body-weight loss and abnormal crypt morphology while increasing epithelial proliferation and Lgr5-lineage crypt regeneration; organoid experiments independently supported improved regenerative capacity with S100A8/A9 inhibition.
- Early injury was also attenuated. Paquinimod reduced TUNEL-positive crypt cells, γ-H2AX, p53, Bax and cleaved caspase-3, increased Bcl-2, lowered oxidative-stress markers and restored glutathione, consistent with less radiation-induced DNA-damage-associated apoptotic stress.
- Barrier recovery improved as well: treated mice had higher ZO-1 and occludin, increased Paneth/goblet-cell measures and lysozyme expression, less macrophage infiltration, lower TNF-α/IL-1β/IL-6 signaling and increased anti-inflammatory IL-10.
- Mechanistically, extracellular S100A8/A9 bound TLR4 and RAGE, activating MAPK and NF-κB signaling and amplifying inflammation, oxidative stress and impaired epithelial repair. The authors caution that S100A8/A9 may have stage-dependent reparative functions in other settings, so prolonged blockade cannot automatically be assumed beneficial.
CLINICAL TAKEAWAY
The study moves S100A8/A9 from being merely a radiation-injury biomarker toward a plausible therapeutic target: its blockade improved both survival and crypt/barrier regeneration in preclinical models. The translation gap is still large—these are mouse and organoid data, and the optimal timing, safety and effect of S100A8/A9 inhibition during human pelvic or abdominal RT are unknown.